Cyclophosphamide,alvocidib (flavopiridol), and rituximab,a novel feasible chemoimmunotherapy regimen for patients with high-risk chronic lymphocytic leukemia

Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study, we combined cyclophosphamide, alvocidib and rituximab (CAR) in a schema designed to mitigate tumor lysis syndrome (TLS) seen previously with alvocidib. Nine nucleoside analog-naïve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted.     

The impact of self- and physician-administered cancer treatment on work productivity and healthcare utilization

Background

Lost productivity in the workplace represents a significant portion of the economic burden of cancer in the United States. Cancer treatments have historically been physician-administered, while recent innovations have led to the development of self-administered, usually oral, agents. Self-administered treatments have the potential to reduce healthcare utilization and time away from work, but the magnitude of these effects is unknown.

The National Lung Screening Trial's Endpoint Verification Process: determining the cause of death

Background

Randomized controlled trials (RCTs) evaluating cancer screening modalities usually employ cause-specific mortality as their primary endpoint. Because death certificate cause of death can be inaccurate, RCTs frequently use review committees to assign an underlying cause of death. We describe the National Lung Screening Trial's (NLST's) death review approach, the Endpoint Verification Process (EVP), which strives to minimize errors in assignment of cause of death due to lung cancer.

Methods

Deaths selected for review include those with a notation of lung cancer on the death certificate and those occurring among participants ever diagnosed with lung cancer. Other criteria that trigger death review include, but are not limited to, death within 6 months of a screen suspicious for lung cancer and death within 60 days of certain diagnostic evaluation procedures associated with a screen suspicious for lung cancer or a lung cancer diagnosis. EVP requires concordance on whether death was due to lung cancer. Deaths are first reviewed by the EVP chair. If concordance is not achieved, the death is next reviewed by an Endpoint Verification Team (EVT) member. If concordance between the chair- and member-assigned cause of death is not achieved, the death is next reviewed by a group of at least three EVT members. Cause of death is assigned at the step in which concordance was achieved, or if necessary, at the team review.

Conclusions

NLST's EVP is designed to produce a highly accurate count of lung cancer deaths.     

Heterogeneity in the definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents: a review of the literature

Aim

There is no consensus about what constitutes a dose-limiting toxicity (DLT) in phase I cancer clinical trials. We aimed to evaluate how DLTs are defined in phase I trials of molecularly targeted agents (MTA).

Methods

We retrieved all phase I trials testing monotherapy with an MTA published over the last decade. In each trial, all items used to define DLTs were recorded.

Results

Reports of 155 phase I trials evaluating 111 different MTAs were reviewed. The most frequent determinant of whether a toxicity was regarded as a DLT was severity, usually assessed using the NCI CTCAE classification. However, for any given toxicity, there was substantial variability in the degree of severity required for a toxicity to be considered a DLT. Specifications about minimum duration of toxicity, degree of reversibility, the need to delay treatment and to reduce dose-intensity because of toxicity were infrequently incorporated in the definition of DLT. The definition of DLT varied with administration schedule. Discrepancies between the initial and the final definition of DLT were reported in 25% of trials.

Conclusions

While our results do not support a standardisation of the definition of DLT, the inclusion of following specifications in its definition when relevant would reduce the heterogeneity observed across trials: (1) DLT assessment period, (2) absolute severity according to NCI CTCAE classification as well as severity relative to baseline status, (3) minimum duration of toxicity, (4) reversibility of toxicity within a certain period of time, and (5) necessity to delay treatment or to reduce dose-intensity.     

Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism

Cancer cells are characterized by self-sufficiency in the absence of growth signals, their ability to evade apoptosis, resistance to anti-growth signals, sustained angiogenesis, uncontrolled proliferation, and invasion and metastasis. Alterations in cellular bioenergetics are an emerging hallmark of cancer. The mitochondrion is the major organelle implicated in the cellular bioenergetic and biosynthetic changes accompanying cancer. These bioenergetic modifications contribute to the invasive, metastatic and adaptive properties typical in most tumors. Moreover, mitochondrial DNA mutations complement the bioenergetic changes in cancer. Several cancer management therapies have been proposed that target tumor cell metabolism and mitochondria. Glycolytic inhibitors serve as a classical example of cancer metabolism targeting agents. Several TCA cycle and OXPHOS inhibitors are being tested for their anticancer potential. Moreover, agents targeting the PDC/PDK (pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase) interaction are being studied for reversal of Warburg effect. Targeting of the apoptotic regulatory machinery of mitochondria is another potential anticancer field in need of exploration. Additionally, oxidative phosphorylation uncouplers, potassium channel modulators, and mitochondrial redox are under investigation for their anticancer potential. To this end there is an increased demand for agents that specifically hit their target. Delocalized lipophilic cations have shown tremendous potential in delivering anticancer agents selectively to tumor cells. This review provides an overview of the potential anticancer agents that act by targeting cancer cell metabolism and mitochondria, and also brings us face to face with the emerging opportunities in cancer therapy.     

A quantitative study of the neuropathology of 32 sporadic and familial cases of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

R. A. Armstrong, D. Carter and N. J. Cairns (2012) Neuropathology and Applied Neurobiology 38, 25–38 A quantitative study of the neuropathology of 32 sporadic and familial cases of frontotemporal lobar degeneration with TDP‐43 proteinopathy (FTLD‐TDP) Aims: To further characterize the neuropathology of the heterogeneous molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA‐binding protein of 43 kDa (TDP‐43) proteinopathy (FTLD‐TDP). Methods: We quantified the neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe using a phosphorylation‐independent TDP‐43 antibody in 32 cases of FTLD‐TDP comprising sporadic and familial cases, with associated pathology such as hippocampal sclerosis (HS) or Alzheimer's disease (AD), and four neuropathological subtypes using TDP‐43 immunohistochemistry. Analysis of variance (anova ) was used to compare differences between the various groups of cases. Results: These data from FTLD‐TDP cases demonstrate quantitative differences in pathological features between: (i) regions of the frontal and temporal lobe; (ii) upper and lower cortex; (iii) sporadic and progranulin (GRN) mutation cases; (iv) cases with and without AD or HS; and (v) between assigned subtypes. Conclusions: The data confirm that the dentate gyrus is a major site of neuropathology in FTLD‐TDP and that most laminae of the cerebral cortex are affected. GRN mutation cases are quantitatively different from sporadic cases, while cases with associated HS and AD have increased densities of dystrophic neurites and abnormally enlarged neurones respectively. There is little correlation between the subjective assessment of subtypes and the more objective quantitative data.